Bioerodible endoprostheses and methods of making the same

ABSTRACT

A bioerodible endoprosthesis erodes by galvanic erosion that can provide, e.g., improved endothelialization and therapeutic effects.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of and claims priority under 35 U.S.C.121 to U.S. application Ser. No. 11/964,969, filed on Dec. 27, 2007,which is a non-provisional of U.S. Provisional Application Ser. No.60/877,693 filed on Dec. 28, 2006, the entire contents of which arehereby incorporated by reference.

TECHNICAL FIELD

The invention relates to bioerodible endoprostheses, and to methods ofmaking the same.

BACKGROUND

The body includes various passageways such as arteries, other bloodvessels, and other body lumens. These passageways sometimes becomeoccluded or weakened. For example, the passageways can be occluded by atumor, restricted by plaque, or weakened by an aneurysm. When thisoccurs, the passageway can be reopened or reinforced with a medicalendoprosthesis. An endoprosthesis is typically a tubular member that isplaced in a lumen in the body. Examples of endoprostheses includestents, covered stents, and stent-grafts.

Endoprostheses can be delivered inside the body by a catheter thatsupports the endoprosthesis in a compacted or reduced-size form as theendoprosthesis is transported to a desired site. Upon reaching the site,the endoprosthesis is expanded, e.g., so that it can contact the wallsof the lumen.

The expansion mechanism may include forcing the endoprosthesis to expandradially. For example, the expansion mechanism can include the cathetercarrying a balloon, which carries a balloon-expandable endoprosthesis.The balloon can be inflated to deform and this to secure the expandedendoprosthesis at a predetermined position in contact with the lumenwall. The balloon can then be deflated, and the catheter withdrawn fromthe lumen.

It is sometimes desirable for an implanted endoprosthesis to erode overtime within the passageway. For example, a fully erodible endoprosthesisdoes not remain as a permanent object in the body, which, in turn, mayhelp the passageway recover to its natural condition. Erodibleendoprostheses can be formed from, e.g., a polymeric material, such aspolylactic acid, or from a metallic material, such as magnesium, iron oran alloy thereof.

SUMMARY

The invention relates to bioerodible endoprostheses and methods ofmaking the endoprostheses. The endoprostheses can be configured to erodein a controlled and predetermined manner in the body.

According to one aspect of the disclosure, a bioerodible endoprosthesiscomprises a relatively electronegative material and a relativelyelectropositive material between which a galvanic cell is formed, and acurrent-controlling coating overlying at least a portion of theendoprosthesis effective to modulate the current or current density ofthe galvanic cell as the endoprosthesis degrades.

Preferred implementations of this aspect of the disclosure may includeone or more of the following additional features. Thecurrent-controlling coating controls exposure of at least one of theelectronegative material and the electropositive material to body fluid.The current-controlling coating has a variable thickness, erosion rate,and/or porosity. The thickness of the current-controlling coating variesalong the axis of the stent, e.g. linearly or non-linearly, e.g.parabolically. The current density increases as a function of time. Thecurrent-controlling coating is a polymer, ceramic or metal. Theendoprosthesis has a body comprising substantially electronegativematerial. The electropositive material is provided as a coating on thebody. The endoprosthesis has a body including electropositive andelectronegative material, and the concentration of each of theelectropositive and electronegative material varies along a length ofthe body. The endoprosthesis comprises a plurality of sections providinga different current or current density, the sections lying along alength of the endoprosthesis. The sections may be substantiallysequentially exposed to body fluid over time.

According to another aspect of the disclosure, an endoprosthesiscomprises a cathode region and an anode region between which a galvaniccell is formed when the endoprosthesis is implanted in the body, and theanode region is degraded by galvanic corrosion such that current densitygenerated by the galvanic cell is maintained between ±10 percent duringdegradation of between about 5 percent to about 50 percent by weight ofthe anode region.

Preferred implementations of this aspect of the disclosure may includeone or more of the following additional features. The endoprosthesisundergoes both galvanic corrosion and bioerosion. Both the cathoderegion and the anode region are bioerodible. The current density issufficient for tumor treatment, restenosis inhibition or promotion ofcell proliferation. The cathode region comprises magnesium or magnesiumalloy, e.g. the magnesium alloy comprises materials selected from thegroup consisting of: zinc, aluminum, magnesium, lithium, iron, nickel,copper, and alloys thereof. The cathode region comprises materialsselected from the group consisting of: iron, platinum, and gold. Theendoprosthesis further comprises a polymer coating. The endoprosthesisfurther comprises a coating selected from the group consisting of:magnesium oxide, magnesium hydride, and magnesium fluoride. Theendoprosthesis erodes from one end toward another end.

According to still another aspect of the disclosure, an erodibleendoprosthesis comprises a body including a relatively electronegativematerial and a relatively electropositive material between which agalvanic cell is formed, the concentration of electronegative andelectropositive material varying along a length of the body.

Preferred implementations of this aspect of the disclosure may includeone or more of the following additional features. The body is formed ofan alloy including the electronegative material and the electropositivematerial. The body includes a current-controlling layer.

Embodiments may have one or more of the following advantages.

An endoprosthesis erodes by galvanic corrosion, producing a controlledcurrent for therapeutic effect. The endoprosthesis may not need to beremoved from a lumen after implantation. The endoprosthesis can have alow thrombogenecity and high initial strength. The endoprosthesis canexhibit reduced spring back (recoil) after expansion. Lumens implantedwith the endoprosthesis can exhibit reduced restenosis. Theendoprosthesis can be erodible. The rate of erosion of differentportions of the endoprosthesis can be controlled, allowing theendoprosthesis to erode in a predetermined manner and reducing, e.g.,the likelihood of uncontrolled fragmentation and embolization. Forexample, the predetermined manner of erosion can be from a first end ofthe endoprosthesis to a second end of the endoprosthesis. The controlledrate of erosion and the predetermined manner of erosion can extend thetime the endoprosthesis takes to erode to a particular degree oferosion, can extend the time that the endoprosthesis can maintainpatency of the passageway in which the endoprosthesis is implanted, canallow better control over the size of the released particles duringerosion, and/or can allow the cells of the implantation passageway tobetter endothelialize around the endoprosthesis.

An erodible or bioerodible endoprosthesis, e.g., a stent, refers to anendoprosthesis, or a portion thereof, that exhibits substantial mass ordensity reduction or chemical transformation after it is introduced intoa patient, e.g., a human patient. Mass reduction can occur by, e.g.,dissolution of the material that forms the endoprosthesis, fragmentingof the endoprosthesis, and/or galvanic reaction. Chemical transformationcan include oxidation/reduction, hydrolysis, substitution, and/oraddition reactions, or other chemical reactions of the material fromwhich the endoprosthesis, or a portion thereof, is made. The erosion canbe the result of a chemical and/or biological interaction of theendoprosthesis with the body environment, e.g., the body itself or bodyfluids, into which the endoprosthesis is implanted and/or erosion can betriggered by applying a triggering influence, such as a chemicalreactant or energy to the endoprosthesis, e.g., to increase a reactionrate. For example, an endoprosthesis, or a portion thereof, can beformed of a relatively electronegative metal (e.g., magnesium, iron) anda relatively electropositive metal (e.g., iron, platinum), which uponimplantation into a body lumen can undergo galvanic erosion. Forexample, an endoprosthesis, or a portion thereof, can be formed from anactive metal, e.g., Magnesium or Calcium or an alloy thereof, and whichcan erode by reaction with water, producing the corresponding metaloxide and hydrogen gas (a redox reaction). For example, anendoprosthesis, or a portion thereof, can be formed from an erodible orbioerodible polymer, an alloy, and/or a blend of erodible or bioerodiblepolymers which can erode by hydrolysis with water. The erosion occurs toa desirable extent in a time frame that can provide a therapeuticbenefit. For example, galvanic erosion of the endoprosthesis can releasea therapeutic ion such as Mg²⁺, which can modulate cell growth forbetter endothelialization of the endoprosthesis. In some embodiments,galvanic erosion provides a therapeutic current, which can be used totreat tumor lesions, promote endothelialization, and/or modulate cellproliferation. For example, the endoprosthesis can exhibit substantialmass reduction after a period of time, when a function of theendoprosthesis, such as support of the lumen wall or drug delivery, isno longer needed or desirable. In particular embodiments, theendoprosthesis exhibits a mass reduction of about 10 percent or more,e.g. about 50 percent or more, after a period of implantation of one dayor more, e.g. about 60 days or more, about 180 days or more, about 600days or more, or 1000 days or less. In embodiments, only portions of theendoprosthesis exhibit erodibility. For example, an exterior layer orcoating may be non-erodible, while an interior layer or body iserodible. In some embodiments, the endoprosthesis includes anon-erodible coating or layer of a radiopaque material, which canprovide long-term identification of an endoprosthesis location.

Erosion rates can be measured with a test endoprosthesis suspended in astream of Ringer's solution flowing at a rate of 0.2 ml/second. Duringtesting, all surfaces of the test endoprosthesis can be exposed to thestream. For the purposes of this disclosure, Ringer's solution is asolution of recently boiled distilled water containing 8.6 gram sodiumchloride, 0.3 gram potassium chloride, and 0.33 gram calcium chlorideper liter of solution.

Other aspects, features and advantages will be apparent from thedescription of the embodiments thereof and from the claims.

DESCRIPTION OF DRAWINGS

FIGS. 1A-1C are sequential, longitudinal cross-sectional views,illustrating delivery of an endoprosthesis in a collapsed state,expansion of the endoprosthesis, and the deployment of theendoprosthesis in a body lumen.

FIGS. 2A-2C are sequential, longitudinal cross-sectional views of anendoprosthesis in a body lumen over time.

FIG. 3 is a schematic drawing illustrating a galvanic reaction in aportion of an endoprosthesis.

FIG. 4 is a cross-sectional view of an embodiment of an endoprosthesis.

FIGS. 5A-5C are longitudinal cross-sectional views of an endoprosthesisin a body lumen over time.

FIG. 6 is a cross-sectional view of an embodiment of an endoprosthesis.

FIG. 7 is a cross-sectional view of an embodiment of an endoprosthesis.

FIG. 8A-8C are sequential, longitudinal cross-sectional views of anembodiment of an endoprosthesis in a body lumen over time.

FIG. 9 is a flow chart of an embodiment of a method of making anendoprosthesis.

FIG. 10 illustrates a method of making an endoprosthesis.

FIG. 11 is a flow chart of an embodiment of a method of making anendoprosthesis.

FIG. 12 is a flow chart of an embodiment of a method of making anendoprosthesis.

DETAILED DESCRIPTION

Referring to FIGS. 1A-1C, during implantation of an endoprosthesis 10,the endoprosthesis is placed over a balloon 12 carried near a distal endof a catheter 14, and is directed through a lumen 15 (FIG. 1A) until theportion of the catheter carrying the balloon and endoprosthesis reachesthe region of an occlusion 18 (FIG. 1B). The endoprosthesis is thenradially expanded by inflating balloon 12 and compressed against thevessel wall with the result that occlusion 18 is compressed, and thevessel wall surrounding it undergoes a radial expansion (FIG. 1B). Thepressure is then released from the balloon and the catheter is withdrawnfrom the vessel (FIG. 1C), leaving the endoprosthesis 10 fixed withinlumen 16.

Referring to FIGS. 2A-2C, the endoprosthesis 10 erodes over a period oftime. For example, in embodiments, the endoprosthesis exhibitssubstantial mass reduction after a period of time when a function of theendoprosthesis, such as support of the lumen wall or drug delivery, isno longer needed or desirable. Referring particularly to FIGS. 2A-2C,for example, the erosion can progress from one end 22 of anendoprosthesis 20 toward a second end 24, which can, for example, enablethe endoprosthesis to maintain patency of a body lumen for a moreprolonged period of time, and/or allow increased endothelialization ofthe endoprosthesis.

Referring particularly to FIG. 3, the endoprosthesis erodes at least inpart by galvanic corrosion in a manner that provides a current densitymagnitude and density uniformity over time to the surrounding tissue,producing a therapeutically beneficial effect. In galvanic corrosion, agalvanic cell 32 is formed that includes a relatively electronegativemetal 34, such as magnesium, in contact with a relativelyelectropositive metal 36, such as platinum. In body fluids, magnesiummetal can act as an anode that is oxidized to Mg²⁺ and two electrons.Mg²⁺ can dissolve into the body environment, and the two electrons aretransferred to platinum, which acts as a cathode. The electrons arereleased to the body environment where they react with oxygen andprotons or water to form water or hydroxyl ions, respectively. Thereleased magnesium ions can, for example, modulate endothelial cellgrowth, which can reduce the chance of restenosis, decrease smoothmuscle cell growth and treat tumor lesions. The therapeutic current canhave a current density of at least about one mA (e.g., at least abouttwo mA, at least about three mA, at least about four mA, at least fivemA, at least six mA, at least seven mA, at least eight mA, or at leastabout nine mA) and/or at most about ten mA (e.g., at most about nine mA,at most about eight mA, at most about seven mA, at most about six mA, atmost about five mA, at most about four mA, at most about three mA, atmost about two mA) at a coulomb dosage of at least about 1 C/cm² (e.g.,from about 5 C/cm², from about 10 C/cm², from about 20 C/cm²) and/or atmost about 25 C/cm² (e.g., at most about 20 C/cm², at most 10 C/cm², atmost 5 C/cm²). In some embodiments, the therapeutic current has acurrent density that is maintained within a desired range for a desiredduration. For example, the current density can be maintained at about±two percent (e.g., at about ±five percent, at about ±10 percent, or atabout ±15 percent) during erosion from about two percent (e.g., fromabout five percent, from about 10 percent, from about 15 percent, orfrom about 20 percent) of the endoprosthesis to about 95 percent (e.g.,to about 90 percent, to about 80 percent, to about 75 percent, to about60 percent, to about 50 percent, to about 40 percent, to about 30percent, to about 20 percent, to about 15 percent, to about 10 percent,or to about five percent) of the endoprosthesis. The effects ofmagnesium ions on endothelial cells is further described, for example,in Maier et al., Biochemica et Biophysica Acta, 1689 (2004), 6-12. Theeffect of electrical current in treatment of tumor lesions is described,for example, in Nilsson et al., Bioelectrochemistry and Bioenergetics,47 (1998), 11-18; and von Euler et al., Bioelectrochemistry, 62 (2004),57-65. The use of current in modulating cell proliferation is described,for example, in Shi et al., Biomaterials, 25 (2004), 2477-2488.

The magnitude, maintenance, and distribution of the current can becontrolled by selecting features such as the geometry, cathode to anodearea ratio, distance between cathode and anode, surface shape andcondition, number of cells, and the application of protectivecurrent-controlling coatings. For example, the galvanic current densityincreases with anode area and decreases with increasing distance fromthe anode-cathode junction. The decrease in current density with respectto the anode-cathode junction can be non-linear.

Referring to FIG. 4, an endoprosthesis 40 has a body 42, which includesa electronegative metal such as magnesium or a magnesium alloy, a thinlayer 46 of electropositive metal, and a current-controlling layer 56.In some embodiments, the endoprosthesis includes a secondcurrent-controlling erodible layer 44 covering the body surface, suchthat the electropositive metal contacts the electronegative metal atselect locations. For example, the electropositive metal directlycontacts the electronegative metal at wells 48, to form a galvaniccouple. The current controlling layer 56 controls and limits the area ofthe electronegative body 42 exposed to body fluid as a function of thedistance along the endoprosthesis from the electropositive layer 46 tomaintain relatively constant current density as the endoprosthesiserodes. The current-controlling layer 56 is an eroding material, e.g. apolymer, and has a thickness that decreases along the endoprosthesis asa function of the distance from the electropositive metal. As currentcontrolling layer 56 erodes, the body 42 is exposed at a predeterminedrate that is a function of the layer thickness. Thus, at regions of thestent more remote from the electropositive layer 46, a larger area ofthe body 42 is exposed and as the body 42 erodes closer to theelectropositive layer 46, a smaller surface area of the body 42 isexposed. Layer 56 can cover a junction 50 between the electronegativebody and the electropositive metal coating to reduce acceleratedgalvanic erosion at the junction. The layer 56 can be made of materialthat erodes more slowly than layer 44, so that the junction is protecteduntil the remainder of the body has eroded.

Referring now to FIGS. 5A, 5B, and 5C, the erosion of the endoprosthesis40 upon implantation into a body lumen 55 is illustrated. Erosion beginsat end 54 and proceeds toward end 52 of the endoprosthesis. Therelatively thin coating of polymer at end 54 can substantially erodebefore erosion of the thicker polymer coating near junction 50, thusgradually exposing the endoprosthesis body to body fluids from end 54 tojunction 50. By tailoring the thickness of the bioerodible polymercoating 56, the area of exposure can decrease as erosion proceeds towardjunction 50 and can help maintain the current density within a desiredrange for a desired duration.

The current-controlling layer can have a linear thickness variation, asillustrated, or a non-linear thickness variation, e.g. a parabolicthickness variation along a length of the stent. For example, thegalvanic current density can decrease exponentially as a function ofincreasing distance between the anode and the cathode, for example, asdescribed in Song et al., Corrosion Science, 46 (2004), 955-977. Thecurrent controlling layer can be erodible, as illustrated above, ornon-erodible. A non-erodible coating can control exposure of the stentbody to body fluid by, e.g. varying porosity along the length of thestent instead of or in addition to thickness variation. The currentcontrolling layer can be, e.g. a polymer, ceramic, or metal. Thecomposition of the current controlling layer can vary along the lengthof the stent. The current controlling layer can also include multiplelayers, such as an erodible layer over a porous, non-erodible layer.Different materials, thicknesses and porosities can be used in differentregions of the stent, such as the interior surface and the exteriorsurface.

Referring to FIG. 6, an endoprosthesis 80 includes an electronegativeerodible body 82 and three sections 84, 86, 88, with varying currentcharacteristics. Each section includes an electropositive metal 92, 92′,92″ and a current controlling layer 94, 94′, 94″. The sections arearranged so that the current density is a lower density at the beginningof the endoprosthesis erosion process (e.g., a long galvanic section)to, for example, promote endothelialization, and a higher currentdensity toward the end of the endoprosthesis erosion process (e.g., ashort galvanic section) to, for example, decrease smooth muscle cellproliferation.

In particular, section 84 has a relatively large electropositive area92″ and electronegative surface area, and occupies a relatively longlength along the stent. The current-controlling layer 94″ is relativelythin, such that it erodes quickly to expose the electronegative andelectropositive metal to body fluid. Section 86 has a smallerelectropositive area 92′ and electronegative area, a shorter length, anda thicker current controlling layer 94′. Section 88 has a still smallerelectropositive area 92 and electronegative area, a shorter length, anda thicker current-controlling layer 94. The sections are exposedsubstantially sequentially, starting with section 84 and proceeding tosection 86 and then section 88, to provide a gradually increasingcurrent density over time.

Referring to FIG. 7, an endoprosthesis 60 has a varying concentration ofelectronegative metal and electropositive metal along its length. Theendoprosthesis has a body formed of an alloy or a composite in which theelectronegative metal gradually decreases in concentration from an end64 toward a second end 66 of the endoprosthesis (shading), while theelectropositive metal can gradually increase in concentration from end64 to end 66. Referring to FIGS. 8A, 8B, and 8C, when implanted into abody lumen 61, endoprosthesis 60 can erode via bio-erosion and galvanicerosion. As shown, the endoprosthesis can erode from end 64 toward end66 over the duration of the lifetime of the endoprosthesis. By tailoringthe concentration of the electronegative metal relative to theconcentration of the electropositive metal along the length ofendoprosthesis, the current density can be maintained within a desiredrage for a desired duration. In embodiments, the endoprosthesis can alsoinclude one or more current-controlling layers (e.g. layers 68) asdiscussed above.

For galvanic corrosion, the endoprosthesis includes at least onerelatively electronegative metal (e.g., magnesium) and at least onerelatively electropositive metal. The relatively electronegative andelectropositive metals form a bimetallic couple, which upon immersion ina biological fluid can form a galvanic cell or a bioelectric batterythat can erode by galvanic corrosion. In some embodiments, theendoprosthesis body includes one or more relatively electronegativemetals in the form of a substantially pure metallic element, an alloy,or a composite. Suitable electronegative metals include metallicelements such as magnesium, iron, zinc, and alloys thereof. Examples ofalloys include magnesium alloys, such as, by weight, 50-98% magnesium,0-40% lithium, 0-5% iron and less than 5% other metals or rare earths;or 79-97% magnesium, 2-5% aluminum, 0-12% lithium and 1-4% rare earths(such as cerium, lanthanum, neodymium and/or praseodymium); or 85-91%magnesium, 6-12% lithium, 2% aluminum and 1% rare earths; or 86-97%magnesium, 0-8% lithium, 2%-4% aluminum and 1-2% rare earths; or8.5-9.5% aluminum, 0.15%-0.4% manganese, 0.45-0.9% zinc and theremainder magnesium; or 4.5-5.3% aluminum, 0.28%-0.5% manganese and theremainder magnesium; or 55-65% magnesium, 30-40% lithium and 0-5% othermetals and/or rare earths. Magnesium alloys are also available under thenames AZ91D, AM50A, and AE42. Other erodible materials are described inBolz, U.S. Pat. No. 6,287,332 (e.g., zinc-titanium alloy andsodium-magnesium alloys); Heublein, U.S. Patent Application 2002000406;Park, Science and Technology of Advanced Materials, 2, 73-78 (2001); andHeublein et al., Heart, 89, 651-656 (2003), all of which are herebyincorporated by reference herein in their entirety. In particular, Parkdescribes Mg—X—Ca alloys, e.g., Mg—Al—Si—Ca, Mg—Zn—Ca alloys.

Suitable electropositive metals include platinum, gold, iridium,aluminum, steel, zinc, and/or alloys thereof. In some embodiments, theelectropositive metal is bioerodible. For example, the electropositivebioerodible metal can be iron and/or zinc. In an endoprosthesis thatincludes bioerodible electronegative and electropositive metals, thebioerodible electropositive metal can be substantially protected fromgalvanic corrosion while the electronegative metal undergoes erosion.Once the electronegative metal has eroded, the bioerodibleelectropositive metal can itself erode, for example, by oxidation or bybio-erosion processes. The electropositive metal can be radiopaque forcompatibility with MRI or fluoroscopic imaging methods. In someembodiments, the relatively electropositive metal has a non-erodibleportion that remains in the body lumen after the remaining portions ofthe endoprosthesis have eroded. The non-erodible portion can providesupport for the body lumen in which the endoprosthesis is implanted.

In some embodiments, the electropositive metal is a thin film on aportion of the endoprosthesis. For example, the electropositive metalcan have a thickness of at most about 500 nanometers (e.g., at mostabout 400 nanometers, at most about 300 nanometers, at most about 200nanometers, at most about 100 nanometers, at most about 80 nanometers,at most about 60 nanometers, at most about 40 nanometers, at most about20 nanometers, at most about 10 nanometers, at most about fivenanometers, at most about two nanometers, or at most about onenanometer) and/or at least about 0.5 nanometer (e.g., at least about onenanometers, at least about two nanometers, at least about fivenanometers, at least about 10 nanometers, at least about 20 nanometers,at least about 40 nanometers, at least about 60 nanometers, at leastabout 80 nanometers, at least about 100 nanometers, at least about 200nanometers, at least about 300 nanometers, or at least about 400nanometers). The electropositive metal can have an area of at leastabout 0.5 mm² (e.g., at least about one mm², at least about two mm², atleast about five mm², at least about 10 mm², at least about 20 mm², atleast about 30 mm², or at least about 40 mm²) and/or at most about 50mm² (e.g., at most about 40 mm², at most about 30 mm², at most about 20mm², at most about 10 mm², at most about five mm², at most about twomm², or at most about one mm²).

In some embodiments, the electropositive metal takes the form of metalclusters on an endoprosthesis body. For example, the electropositivemetal can be in a cluster of at least about 10 atoms (e.g., at leastabout 50 atoms, at least about 100 atoms, at least about 500 atoms, atleast about 1,000 atoms, at least about 10,000 atoms) and/or at mostabout 100,000 atoms (e.g., at most about 10,000 atoms, at most about1,000 atoms, at most about 500 atoms, at most about 100 atoms, or atmost about 50 atoms). The metal cluster can have an area of at leastabout 1 nm² (e.g., at least about 10 nm², at least about 100 nm², atleast about 1,000 nm², at least about 10,000 nm²) and/or at most about 1μm² (e.g., at most about 10,000 nm², at most about 1,000 nm², at mostabout 100 nm², or at most about 10 nm²). In some embodiments, the metalclusters form microarrays on the endoprosthesis. For example, the metalclusters can have a density of from about 10 metal clusters per mm²(e.g., about 100 metal clusters per mm², or about 1,000 metal clustersper mm²) to about 10,000 metal clusters per mm² (e.g., about 1,000 metalclusters per mm², or about 100 metal clusters per mm²) of the surface ofthe endoprosthesis.

In some embodiments, the electropositive metal occupies a fraction ofthe endoprosthesis. For example, the electropositive metal can be atleast about one percent by weight (e.g., at least about 10 percent byweight, at least about 20 percent by weight, at least about 30 percentby weight, at least about 40 percent by weight, at least about 50percent by weight, at least about 60 percent by weight, at least about70 percent by weight, or at least about 80 percent by weight) and/or atmost about 90 percent by weight (e.g., at most about 80 percent byweight, at most about 70 percent by weight, at most about 60 percent byweight, at most about 50 percent by weight, at most about 40 percent byweight, at most about 30 percent by weight, at most about 20 percent byweight, or at most about 10 percent by weight) of the endoprosthesis.

In embodiments, the endoprosthesis body includes more than one material,such as different bioerodible materials physically mixed together,multiple layers of different bioerodible materials, and/or multiplesections of different bioerodible materials along a direction (e.g.,length) of the tube. For example, the endoprosthesis body can include amixture of a magnesium alloy in a bioerodible polymer, in which two ormore distinct substances (e.g., metals, ceramics, glasses, and/orpolymers) are intimately combined to form a complex material. Inaddition to galvanic corrosion, the endoprosthesis can undergo directbioerosion of the electropositive, electronegative and/or coatingmaterial.

The current controlling layer provides a barrier that limits or preventsexposure of the stent body and/or electropositive material. Suitablematerials include oxides, hydrides, or fluorides. Examples of polymersinclude bioerodible polymers such as polylactic acid (PLA), polylacticglycolic acid (PLGA), polyanhydrides (e.g., poly(ester anhydride)s,fatty acid-based polyanhydrides, amino acid-based polyanhydrides),polyesters, polyester-polyanhydride blends, polycarbonate-polyanhydrideblends, and/or combinations thereof. The layer can have a thickness ofat least about one nanometer (e.g., at least about 10 nanometers, atleast about 100 nanometers, at least about one micrometer, or at leastabout five micrometers) and/or at most about 10 micrometers (e.g., atmost about five micrometers, at most about one micrometer, at most about100 nanometers, at most about 10 nanometers). The thickness can beuniform or non-uniform. For example, the thickness can increase from oneend of the endoprosthesis to another end in an overall linear manner, anoverall non-linear manner (e.g., an overall parabolic increase, anoverall exponential increase), or a stepwise manner. The thickness ofthe polymeric layer at a given location on the endoprosthesis can becorrelated with the desired current density. For example, a thickerpolymer layer which erodes over a longer period of time can attenuate arelatively high current density by decreasing the rate of exposure ofthe electronegative metal cathode to body fluids. A thinner polymerlayer which erodes over a shorter period of time can compensate for arelatively low current density by increasing the rate of exposure of theelectronegative metal cathode to body fluids. In some embodiments, thelayer partially covers the endoprosthesis body. For example, the layercan cover at least about 10 percent (e.g., at least about 20 percent, atleast about 30 percent, at least about 40 percent, at least about 50percent, at least about 60 percent, at least about 70 percent, at leastabout 80 percent, at least about 90 percent, or at least about 95percent) and/or at most 100 percent (e.g., at most about 95 percent, atmost about 90 percent, at most about 80 percent, at most about 70percent, at most about 60 percent, at most about 50 percent, at mostabout 40 percent, at most about 30 percent, or at most 20 percent) ofthe surface area of the endoprosthesis body.

Referring to FIG. 9, a method 200 of making an endoprosthesis 40 asdescribed herein is shown. Method 200 includes forming a bioerodibletube, e.g. by cutting a tube (step 202), forming a pre-endoprosthesisfrom the bioerodible tube (step 204), applying a current-controllinglayer, e.g. an oxide coating (step 206), forming an anode on theendoprosthesis tube (step 208), and/or applying a current-controllingpolymer layer to the pre-endoprosthesis (step 210) to form anendoprosthesis. In some embodiments, one or more current-controllinglayers are applied to the bioerodible tube, and the tube with theapplied current-controlling layers is subsequently formed into anendoprosthesis.

The bioerodible tube can be formed (step 202) by manufacturing a tubularmember capable of supporting a bodily lumen including (e.g., is formedof) one or more bioerodible electronegative metals. For example, a massof bioerodible metal can be machined into a rod that is subsequentlydrilled to form the tubular member. As another example, a sheet ofbioerodible metal can be rolled to form a tubular member withoverlapping portions, or opposing end portions of the rolled sheet canbe joined (e.g., welded) together to form a tubular member. Abioerodible metal can also be extruded to form a tubular member. Incertain embodiments, a bioerodible tube is made by thermal spraying,powder metallurgy, thixomolding, die casting, gravity casting, and/orforging.

As shown in FIG. 9, after the bioerodible tube is formed, the tube isformed into a pre-endoprosthesis (step 204). In some embodiments,selected portions of the tube are removed to form circular andconnecting struts by laser cutting, as described in U.S. Pat. No.5,780,807, by Saunders, hereby incorporated by reference in itsentirety. Other methods of removing portions of the tube can be used,such as mechanical machining (e.g., micro-machining, grit blasting orhoning), electrical discharge machining (EDM), and photoetching (e.g.,acid photoetching). The pre-endoprosthesis can be etched and/orelectropolished to provide a selected finish. In certain embodiments,such as jelly-roll type endoprostheses, step 204 may be omitted.

In some embodiments, the current-controlling layer(s) such as an oxide,a hydride, and/or a fluoride layer is formed on the pre-endoprosthesis(step 206). Prior to applying the layer(s), selected surfaces (e.g.,interior surface) or portions (e.g., portion between the end portions ofthe endoprosthesis) of the pre-endoprosthesis can be masked so that thecurrent-controlling layer will not be applied to the masked surfaces orportions. General methods of forming coatings are described, forexample, in Gray et al., Journal of Alloys and Compounds, 336 (2002),88-113. A current-controlling layer such as an oxide layer can be formedon the surface of the bioerodible tube by exposing the tube to air atambient or elevated temperatures, for example, as described in You etal., Scripta mater, 42 (2000), 1089-1094. In some embodiments, an oxidelayer is deposited using plasma immersion ion implantation as described,for example, in Wan et al., South Jiaotong University, Chengdu, 2005;and Gray et al., Journal of Alloys and Compounds, 336 (2002), 88-113.Methods of forming oxide, hydride, and/or fluoride layers include vacuumarc deposition, as described for example, in Gust et al., Thin SolidFilms, 383 (2001), 224-226; and electrochemical ion reduction and plasmaimmersion ion implantation, as described, for example, in Bakkar et al.,Corrosion Science, 47 (2005), 1211-1225 and in U.S. Provisional PatentApplication No. 60/862,318, filed Oct. 20, 2006. The mask can be removedunder ambient or inert atmosphere prior to proceeding to the subsequentstep.

Referring to step 208, the anode is formed on a portion of theendoprosthesis. The anode layer can be deposited onto a portion of theendoprosthesis by pulsed laser deposition, for example, as described inWang et al., Thin Solid films, 471 (2005) 86-90. The anode can directlycontact the cathode material in the endoprosthesis body at certainportions, for example, where the endoprosthesis was masked prior tocurrent-controlling layer formation. In some embodiments, to obtainelectrical contact between the anode layer and the cathode, a laser isused to form wells (e.g., wells 48) in the endoprosthesis under inertatmosphere, and the wells can be filled with the anode material bypulsed laser deposition such that at least a portion of the anodematerial directly contacts the cathode material. In some embodiments,the anode is in the form of metal cluster arrays. Arrays can be formed,for example, by electroless plating and lithographic methods.

As shown in step 210, in some embodiments, a current-controlling polymerlayer is then applied to one or more portions of the endoprosthesis. Thepolymer layer can cover the junction at which the anode meets theendoprosthesis body to reduce galvanic corrosion at the junction.Depending on the polymer, one or more polymers can be dissolved in asolvent and applied to the pre-endoprosthesis. In some embodiments, forexample, polymer layers are deposited by dip coating, electrostaticspraying, conventional air atomization spraying, and/or layer-by-layerdeposition. In certain embodiments, patterns are generated in a polymerlayer, e.g., by laser ablation, lithography, ink jet printing, and/orscreen printing. The polymer layer can have variable thicknesses alongthe length of the endoprosthesis. For example, the endoprosthesis can bedip-coated into a polymer solution at progressively decreasing depths toobtain a tapered polymer coating formed of many layers; the polymer canbe coated to a uniform thickness and the variable thickness can beobtained by ablating sections of the polymer; the polymer can be coatedusing layer-by-layer deposition at select locations to obtain variablethicknesses. In some embodiments, an endoprosthesis has greater than onetype of polymer layer located at the same or different locations on theendoprosthesis. For example, within a polymer layer, the thickness andcomposition of the polymers can be the same or different to providedesired erosion rates and erosion sequence. For example, theintermediate portion of an endoprosthesis can have a larger thickness ofa slowly erodible first polymer and the end portions of theendoprosthesis can contain a smaller thickness of a quickly erodiblesecond polymer. The erosion directionality can allow for increasedmaintenance of patency for certain locations (e.g., weakened locations)in a body vessel. The polymer layers can be applied the same way or indifferent ways. For example, a first, innermost polymer layer can bespray-coated on the pre-endoprosthesis, and a second, outer polymerlayer can include a polymer that is dip-coated onto the first layer.

Referring now to FIG. 10, an endoprosthesis having an increasing numberof different polymer layers along its length can be produced from ametallic pre-endoprosthesis 240 by masking selective portions of theendoprosthesis. For example, during production, all portions of thepre-endoprosthesis can be coated 248 with a first polymer layer togenerate a pre-endoprosthesis 250. Next, a portion of thepre-endoprosthesis is masked 252 (e.g., with a protective polymericcoating such as a styrene-isoprene-butadiene-styrene (SIBS) polymer),which protects the masked portion from further polymer layer coating,and the remaining section is coated 254 with a second polymer layer tomake a pre-endoprosthesis 270. Finally, a second portion of thepre-endoprosthesis is masked 272, and the remaining portion is furthercoated 274 with a third polymer layer to make pre-endoprosthesis 290.The protective coatings can be removed, e.g., by rinsing 295 in asolvent in which only the masking polymer is soluble to affordendoprosthesis 300.

In some embodiments, the endoprosthesis has both exterior and interiorsurfaces coated with the polymer layer(s). In some embodiments, prior toapplying the polymer layer(s), the interior surface or the exteriorsurface of the bioerodible tube is masked (e.g., by using a mandrel inthe interior of the tube or a tight-fitting tube on the exterior of thetube) to apply the polymer layer(s) to only selected portion(s) of thetube.

In some embodiments, a medicament is incorporated into a polymer coatingon an endoprosthesis. For example, a medicament can be adsorbed onto apolymer on an endoprosthesis. A medicament can be encapsulated in abioerodible material and embedded in an polymer coating on anendoprosthesis. As another example, a medicament can be dissolved in apolymer solution and coated onto an endoprosthesis.

Referring to FIG. 11, in some embodiments, the pre-endoprosthesis is cut(step 230) to form the endoprosthesis after formation of the bioerodibletube (step 222), current-controlling oxide coating (step 224), formationof the anode (step 226), and current-controlling polymer layerapplication (step 228).

Referring to FIG. 12, in some embodiments, a bioerodible tube is formedas previously described using a first material such as one or morerelatively electronegative or electropositive metals. Acounter-electrode is formed (step 314) in the bioerodible tube by makinga gradient of a second material, such as one or more bioerodible metals,by plasma immersion ion implantation. Plasma immersion ion implantationis described, for example, in Wan et al., South Jiaotong University,Chengdu, 2005; and Gray et al., Journal of Alloys and Compounds, 336(2002), 88-113. The first and second bioerodible materials form agalvanic couple. One or more current-controlling coatings (e.g., oxide,hydride, and/or fluoride layer) and/or one or more current-controllingpolymer layers are then applied to the bioerodible tube (steps 316 and318). Selected portions of the bioerodible tube can then be removed(step 320), for example, to afford struts in the final endoprosthesis.In some embodiments, removal of selected portions of the bioerodibletube occurs before or after formation of the counter-electrode gradient.

In use, the endoprostheses can be used, e.g., delivered and expanded,using a catheter delivery system, such as a balloon catheter system.Catheter systems are described in, for example, Wang U.S. Pat. No.5,195,969, Hamlin U.S. Pat. No. 5,270,086, and Raeder-Devens, U.S. Pat.No. 6,726,712. Endoprosthesis and endoprosthesis delivery are alsoexemplified by the Radius® or Symbiot® systems, available from BostonScientific Scimed, Maple Grove, Minn.

The endoprostheses described herein can be of a desired shape and size(e.g., coronary stents, aortic stents, peripheral vascular stents,gastrointestinal stents, urology stents, and neurology stents).Depending on the application, the stent can have a diameter of between,for example, 1 mm to 46 mm. In certain embodiments, a coronary stent hasan expanded diameter of from about 2 mm to about 6 mm. In someembodiments, a peripheral stent has an expanded diameter of from about 5mm to about 24 mm. In certain embodiments, a gastrointestinal and/orurology stent has an expanded diameter of from about 6 mm to about 30mm. In some embodiments, a neurology stent has an expanded diameter offrom about 1 mm to about 12 mm. An abdominal aortic aneurysm (AAA) stentand a thoracic aortic aneurysm (TAA) stent can have a diameter fromabout 20 mm to about 46 mm.

While a number of embodiments have been described, the invention is notso limited.

In some embodiments, depending on the location of the anode and thecathode, the endoprosthesis is configured to erode sequentially from aninterior cathode surface to an exterior anode surface, from an exteriorcathode surface to an interior anode surface, from a center cathodeportion to an exterior and an interior anode portions, or from anexterior and an interior cathode portion to a center anode portion.These constructions can allow the endoprosthesis to support the bodyvessel initially using the strength of multiple layers, and to reduce inthickness over time (e.g., after cells have endothelialized theendoprosthesis). The reduction in thickness can enhance the flexibilitythe endoprosthesis to better match the natural state of the body vessel.

The endoprostheses described herein can be a part of a stent, a coveredstent or a stent-graft. For example, an endoprosthesis can includeand/or be attached to a biocompatible, non-porous or semi-porous polymermatrix made of polytetrafluoroethylene (PTFE), expanded PTFE,polyethylene, urethane, or polypropylene.

The endoprostheses described herein can include non-metallic structuralportions, e.g., polymeric portions. The polymeric portions can beerodible. The polymeric portions can be formed from a polymeric alloy.Polymeric stents have been described in U.S. patent application Ser. No.10/683,314, filed Oct. 10, 2003; and U.S. patent application Ser. No.10/958,435, filed Oct. 5, 2004, the entire contents of each of which isincorporated by herein reference.

The endoprostheses can include a releasable therapeutic agent, drug, ora pharmaceutically active compound, such as described in U.S. Pat. No.5,674,242, U.S. patent application Ser. No. 09/895,415, filed Jul. 2,2001, U.S. patent application Ser. No. 11/111,509, filed Apr. 21, 2005,and U.S. patent application Ser. No. 10/232,265, filed Aug. 30, 2002.The therapeutic agents, drugs, or pharmaceutically active compounds caninclude, for example, anti-thrombogenic agents, antioxidants,anti-inflammatory agents, anesthetic agents, anti-coagulants, andantibiotics. The therapeutic agent, drug, or a pharmaceutically activecompound can be dispersed in a polymeric coating carried by theendoprosthesis. The polymeric coating can include more than a singlelayer. For example, the coating can include two layers, three layers ormore layers, e.g., five layers. The therapeutic agent can be a genetictherapeutic agent, a non-genetic therapeutic agent, or cells.Therapeutic agents can be used singularly, or in combination.Therapeutic agents can be, for example, nonionic, or they may be anionicand/or cationic in nature. An example of a therapeutic agent is one thatinhibits restenosis, such as paclitaxel. The therapeutic agent can alsobe used, e.g., to treat and/or inhibit pain, encrustation of theendoprosthesis or sclerosing or necrosing of a treated lumen. Any of theabove coatings and/or polymeric portions can be dyed or renderedradio-opaque.

The endoprostheses described herein can be configured for non-vascularlumens. For example, it can be configured for use in the esophagus orthe prostate. Other lumens include biliary lumens, hepatic lumens,pancreatic lumens, uretheral lumens and ureteral lumens.

All references, such as patent applications, publications, and patents,referred to herein are incorporated by reference in their entirety.

Other embodiments are within the claims.

What is claimed is:
 1. An endoprosthesis, comprising: a cathode regionand an anode region between which a galvanic cell is formed when theendoprosthesis is implanted in the body, and the anode region isdegraded by galvanic corrosion; and a current controlling layer thaterodes to control and limit an area of the anode region exposed to bodyfluid such that current density generated by the galvanic cell ismaintained between ±10 percent during degradation of between 5 percentto 50 percent by weight of the anode region.
 2. The endoprosthesis ofclaim 1, wherein the endoprosthesis undergoes both galvanic corrosionand bioerosion.
 3. The endoprosthesis of claim 1, wherein both thecathode region and the anode region are bioerodible.
 4. Theendoprosthesis of claim 1, wherein the current density is sufficient fortumor treatment, restenosis inhibition or promotion of cellproliferation.
 5. The endoprosthesis of claim 1, wherein the cathoderegion comprises magnesium or magnesium alloy.
 6. The endoprosthesis ofclaim 5, wherein the magnesium alloy comprises materials selected fromthe group consisting of: zinc, aluminum, magnesium, lithium, iron,nickel, copper, and alloys thereof.
 7. The endoprosthesis of claim 1,wherein the cathode region comprises materials selected from the groupconsisting of: iron, platinum, and gold.
 8. The endoprosthesis of claim1, further comprising a polymer coating.
 9. The endoprosthesis of claim1, further comprising a coating selected from the group consisting of:magnesium oxide, magnesium hydride, and magnesium fluoride.
 10. Theendoprosthesis of claim 1, wherein the endoprosthesis erodes from oneend toward another end.
 11. An erodible endoprosthesis, comprising: abody including a relatively electronegative material and a relativelyelectropositive material between which a galvanic cell is formed, thebody being formed of an alloy including the electronegative material andthe electropositive material, the concentration of electronegative andelectropositive material varying in the alloy along a length of thebody, wherein concentrations of the electronegative and theelectropositive materials are tailored along the length such that, whenexposed to body fluid, a current density is generated and maintainedbetween ±10 percent during degradation of between 5 percent to 50percent by weight of the endoprosthesis.
 12. The endoprosthesis of claim11, wherein the body includes a current-controlling layer.